PROCESS FOR PREPARING AMINOBENZOYLBENZOFURAN DERIVATIVES
The present invention relates generally to the preparation of
amino-benzoyl-benzofuran derivatives.
More specifically, the invention relates to a process for the
preparation of 5-amino-benzoyl-benzofuran derivatives of
general formula:

in which R1 represents hydrogen or an alkyl group and R2
represents hydrogen or an alkyl, alkoxy or dialkylaminoalkoxy
group.
In the above formula I:
• R1 represents in particular a linear or branched C1-C8 alkyl
group, in particular a linear or branched C1-C4 alkyl group,
such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl
or tert-butyl,
• R2 represents in particular a linear or branched C1-C9 alkyl
group, in particular a linear or branched C1-C4 alkyl group,
such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl
or tert-butyl; a linear or branched C1-C8 alkoxy group, in
particular a linear or branched C1-C4 alkoxy group, such as
methoxy, ethoxy, n-propoxy, isoproxy, n-butoxy, sec-butoxy or
tert-butoxy; or also a dialkylaminoalkoxy group in which each
linear or branched alkyl group is a C1-C8 alkyl group and the
linear or branched alkoxy group is a C1-C8 alkoxy group, in
particular in which each linear or branched alkyl group is a C1-

C4 alkyl group, such as methyl, ethyl, n-propyl, isopropyl, n-
butyl, sec-butyl or tert-butyl, and the linear or branched
alkoxy group is a C1-C4 alkoxy group, such as methoxy, ethoxy,
n-propoxy, isopropoxy, n-butoxy, sec-butoxy or tert-butoxy.
Preferably, R1 represents n-butyl and R2 represents 3-[di(n-
butyl)amino]propoxy.
The compounds of formula I above are, for the most part,
compounds described in patent EP 0 471 609, where they are
presented as intermediates in the final preparation of
aminoalkoxybenzoyl-benzofuran derivatives of use for their
therapeutic applications in the cardiovascular field.
Among these aminoalkoxybenzoyl-benzofuran derivatives, 2- (n-
butyl)-3-(4-{3-[di(n-butyl)amino]propoxy}benzoyl)-5-
(methanesulfonamido)benzofuran, commonly referred to as
dronedarone, and its pharmaceutically acceptable salts, has
proven to be particularly advantageous, in particular as
antiarrhythmic agent.
A process for the preparation of dronedarone was reported in
the abovesaid patent EP 0 471 609, according to which process
2-(n-butyl)-3-(4-{3-[di(n-butyl)aminojpropoxy}benzoyl)-5-
nitrobenzofuran is reduced under pressure with hydrogen in the
presence of platinum oxide as catalyst to form 2- (n-butyl)-3-
(4-{3-[di(n-butyl)amino]propoxy}benzoyl)-5-aminobenzofuran
(hereinafter Compound A) , which is subsequently treated with
methanesulfonyl chloride, in the presence of an acid acceptor,
to give the desired compound. According to this process,
dronedarone could be obtained with an overall yield of the
order of 60%, starting from the 5-nitrobenzofuran derivative.
However, this process is not devoid of disadvantages
inherent in particular in the type of reaction used in the
formation of Compound A, namely a hydrogenation under pressure,
which has an industrial risk.
Moreover, this method requires the isolation of Compound A
from its formation medium, the isolation of this compound,

normally in the form of its oxalate, consequently constituting
an additional stage in the preparation of dronedarone.
The search for an industrial preparation process capable of
overcoming these disadvantages while offering high yields of
Compound A and also facilitated use of the latter, so as to
produce significantly greater yields of dronedarone with
respect to the prior process, consequently remains of
indisputable interest.
In point of fact, it has now been found that Compound A can
be prepared according to a process involving a selective
reduction of its nitro functional group with respect to its
ketone functional group. This selective reduction consequently
eliminates the need to isolate this Compound A via its oxalate
during the final synthesis of dronedarone, which can be
obtained in this way with overall yields of greater than 90%
from the starting 5-nitrobenzofuran derivative.
The aminoalkoxybenzoyl-benzofuran derivatives of patent EP 0
471 609, in particular dronedarone, can consequently be
synthesized in the very medium for formation of the appropriate
compound of formula I.
According to a first subject matter of the invention, the 5-
aminobenzofuran derivatives of formula I can be prepared by
reducing a 5-nitrobenzofuran derivative of general formula:

in which R1 and R2 have the same meanings as above, by means of
a hydrogen-transfer agent, in the presence of palladium-on-
charcoal as catalyst and in an ether or a mixture of ethers as
solvent, which forms the desired compounds.

In the above formula II, R1 preferably represents n-butyl
and R2 preferably represents 3-[di (n-butyl)amino]propoxy.
In addition, according to another of its subject matters,
the invention relates to a process for the preparation of
sulfonamidobenzofuran derivatives of general formula:

and of their pharmaceutically acceptable salts, in which R1 and
R2 have the same meanings as above and R3 represents an alkyl
group, according to which process:
a) a 5-nitrobenzofuran derivative of formula II is reduced by
means of a hydrogen-transfer agent, in the presence of
palladium-on-charcoal as catalyst and in an ether or a mixture
of ethers as solvent, in order to form a reaction medium
comprising a 5-amino-benzoyl-benzofuran derivative of formula I
above, in the free base form,
b) the reaction medium comprising the 5-amino-benzoyl-
benzofuran derivative of formula I in the free base form
obtained above is treated with a halide of general formula:

in which Hal represents a halogen, such as chlorine, and R3 has
the same meaning as above, in the presence of a basic agent, in
order to obtain the desired compounds in the free base form,
which are reacted, if necessary, with an organic or inorganic
acid in order to form a pharmaceutically acceptable salt of
this desired compound.

Subsequently, the pharmaceutically acceptable salt of the
compound of formula III can be recovered from its formation
medium, for example by crystallisation.
In the above formula III, R3 represents in particular a linear
or branched C1-C8 alkyl group, in particular a linear or
branched C1-C4 alkyl group, such as methyl, ethyl, n-propyl,
isopropyl, n-butyl or tert-butyl,
Preferably, R1 represents n-butyl, R2 represents 3-[di(n-
butyl) amino] propoxy and R3 represents methyl in the above
formula III.
The hydrogen transfer reduction according to the invention is
normally carried out in an ether or a mixture of ethers as
solvent, in contrast to the state of the art, where this type
of reaction is generally carried out in an alcohol. This
reduction in an ether or a mixture of ethers makes possible in
particular a significant chemoselectivity of the nitro
functional group at the expense of the ketone functional group
which is also present and which is itself also capable of a
reduction to give alcohol. This selective reduction of the
nitro functional group consequently avoids the isolation of the
compound of formula I in whatever way this is done, in
particular by conversion of this compound, obtained in basic
form, into a salt which can be easily separated from its
formation medium.
The ether used as solvent is usually a dialkyl ether, such as
methyl tert-butyl ether, or a cyclic ether, for example
tetrahydrofuran, while the mixture of ethers generally
corresponds to a mixture of dialkyl ether and of cyclic ether,
for example a mixture of methyl tert-butyl ether and of
tetrahydrofuran.
Methyl tert-butyl ether represents a solvent which is
particularly preferred in the context of the present invention,
in particular for the preparation of Compound A and
subsequently of dronedarone.

Usually, the hydrogen-transfer agent is a formate, preferably
ammonium formate, or a phosphinate, in particular sodium
phosphinate. This hydrogen-transfer agent is used in excess
with respect to the compound of formula II, it being possible
for this excess to reach from 3 to 5 equivalents, or more, of
hydrogen-transfer agent per equivalent of compound of formula
II. Preferably, 5 or approximately 5 equivalents of hydrogen-
transfer agent are used per equivalent of compound of formula
II, for example 5 or approximately 5 equivalents of hydrogen-
transfer agent dissolved, for example, in a volume of water. In
particular, 5 equivalents of ammonium formate dissolved, for
example, in a volume of water are used.
The reduction can take place at ambient temperature. However,
the reduction is generally undertaken by heating the reaction
medium at a temperature ranging up to, for example, from 50°C
to 60°C, preferably at a temperature of the order of 40°C, in
particular at 4 0°C.
According to one of its specific aspects, the invention
additionally relates to a process for the preparation of 2- (n-
butyl)-3-(4-{3-[di(n-butyl)amino]propoxy}benzoyl)-5-
aminobenzofuran, according to which process 2-(n-butyl)-3-(4-
{3-[di(n-butyl)amino]propoxy}benzoyl}-5-nitrobenzofuran is
reduced by means of ammonium formate or sodium phosphinate as
hydrogen-transfer agent, in the presence of palladium-on-
charcoal as catalyst and in methyl tert-butyl ether or a
mixture of methyl tert-butyl ether and of tetrahydrofuran as
solvent, to form a reaction medium comprising 2-(n-butyl)-3-(4-
{3-[di(n-butyl)amino]propoxy}benzoyl}-5-aminobenzofuran in the
free base form.
Moreover, according to another of its specific aspects, the
invention relates to a process for the preparation of 2- (n-
butyl)-3-(4-{3-[di(n-butyl}amino]propoxy}benzoyl}-5-
(methanesulfonamido)benzofuran or dronedarone and of its
pharmaceutically acceptable salts, according to which process:

a) 2-(n-butyl)-3-(4-{3-[di(n-butyl)amino]propoxy}benzoyl}-5-
nitrobenzofuran is reduced by means of ammonium formate or
sodium phosphinate as hydrogen-transfer agent, in the presence
of palladium-on-charcoal as catalyst and in methyl tert-butyl
ether or a mixture of methyl tert-butyl ether and of
tetrahydrofuran as solvent, in order to form a reaction medium
comprising 2- (n-butyl)-3-(4-{3- [di(n-
butyl)amino]propoxy}benzoyl)-5-aminobenzofuran in the free base
form,
b) the reaction medium comprising the 2-(n-butyl)-3-(4-{3-
[di(n-butyl)amino]propoxy}benzoyl)-5-aminobenzofuran in the
free base form obtained above is treated with a methanesulfonyl
halide in the presence of a basic agent, in order to obtain the
dronedarone in the basic form, which is reacted, if necessary,
with an organic or inorganic acid in order to form a
pharmaceutically acceptable salt of dronedarone.
Subsequently, the pharmaceutically acceptable salt of
dronedarone can be recovered from its formation medium, for
example by crystallisation.
In the light of the preceding description, the combination
formed by a 5-nitrobenzofuran derivative of formula II, a
hydrogen-transfer agent, palladium-on-charcoal and an ether or
a mixture of ethers as solvent proves to be particularly
advantageous as reaction medium for the preparation of various
compounds, in particular the compounds of formula I and those
of formula III above.
Consequently, another subject matter of the invention
relates to a reaction medium, characterized in that it is
formed:
a) of a 5-nitrobenzofuran derivative of formula II, in
particular a derivative of formula II in which R1 represents n-
butyl and R2 represents 3-[di(n-butyl)amino]propoxy,
b) of a hydrogen-transfer agent, such as ammonium formate or
sodium phosphinate,
c) of palladium-on-charcoal,

d) of an ether, such as methyl tert-butyl ether, or of a
mixture of ethers, such as a mixture of methyl tert-butyl ether
and of tetrahydrofuran, as solvent.
The following non-limiting example illustrates the
preparation of a compound of formula I according to the process
of the invention and also its use in the synthesis of
dronedarone.
EXAMPLE
a) 2-(n-Butyl)-3-(4— {3 3—[di(n-butyl)amino]propoxy)benzoyl)-5-
aminobenzofuran (Compound A or compound of formula I: R1 = n-C4H9; R2
= 3-[di(n-butyl)amino]propoxy)
3.33 kg of a 30% solution of 2-(n-butyl)-3-(4-{3-[di(n-
butyl)amino]propoxy}benzoyl)-5-nitrobenzofuran (compound of
formula II) and 0.05 kg of dry palladium-on-charcoal (Pd/C) are
charged to a 5 1 reactor at ambient temperature. The combined
mixture is heated, with stirring, to 40°C and then a solution
of 0.62 kg (5 equivalents) of ammonium formate in 0.62 kg of
water is added over approximately 2 h. The temperature of the
reaction medium is then maintained at 40 °C ( + /-2°C) for 15 h
while monitoring the progress of the reaction by liquid
chromatography. As soon as the reduction is complete, the
mixture is cooled to 23°C (+ /-2°C) and then the palladium-on-
charcoal is filtered off and then washed with methyl tert-butyl
ether and water. Separation by settling is then carried out at
ambient temperature and the organic phase is washed with water.
These operations of separation by settling and washing are
subsequently repeated once. A further separation by settling is
carried out and the solution is concentrated at 40°C under
vacuum. The concentrate is subsequently diluted with
tetrahydrofuran, which provides 3.47 kg of a solution of the
desired compound in a mixture of methyl tert-butyl ether and of
tetrahydrofuran.

Estimated yield: 99%
b) Dronedarone hydrochloride (hydrochloride of the compound of
formula III: R1= n-C4H9; R2= 3- [di (n-butyl) amino]propoxy; R3= CH3)
The 3.47 kg of solution of Compound A in a mixture of methyl
tert-butyl ether and of tetrahydrofuran obtained above is
charged to a 5 1 reactor at ambient temperature. The
methanesulfonyl chloride is subsequently added over 1 h with
stirring while maintaining the temperature of the reaction
medium below 30°C. Cooling is carried out to 25°C and then an
aqueous ammonia solution. is run in, the temperature of the
reaction medium being maintained at 25 °C. The end of the
reaction is monitored by liquid chromatography. Water and
methyl tert-butyl ether are then added to the reaction medium,
maintained at 30°C, and stirring is maintained for 15 min.
After separation by settling, the organic phase is washed,
first with an aqueous saline solution. Stirring is maintained
at 28°C for 10 min, separation by settling is then carried out
and the organic phase is concentrated at 45°C under vacuum.
Isopropanol is then added and the solution is concentrated at
50°C under vacuum. Isopropanol is again added and the solution
is again concentrated at 50°C under vacuum. The reaction medium
is adjusted by addition of 2.03 kg of isopropanol, so as to
obtain 3.62 kg of a solution, in isopropanol, of the desired
compound in the base form. This solution is heated to 50 °C,
0.225 kg of hydrochloric acid is then added to the reaction
medium, maintained at a temperature of 50 °C to 55°C, and then
the crystallization of the desired hydrochloride is initiated
by addition of dronedarone hydrochloride to the reaction
medium. The product is subsequently filtered off and the
filtration cake is washed with isopropanol, which provides the
desired hydrochloride, which is dried at 45°C under vacuum in
order to obtain 1.12 kg of dry dronedarone hydrochloride.
Overall yield (with respect to the compound I): 96%

The process according to the invention exhibits indisputable
advantages in comparison with the method described in patent EP
0 471 609 or patent application WO 2002/048078.
This is because the nitro functional group of the compound
of formula II can be reduced in a standard reactor, which
avoids the need to operate with hydrogen under pressure in a
hydrogenation device. Moreover, the quality of the compound of
formula I in the base form is found to be significantly
improved since a reduced number of various impurities are
recorded as being formed, and in smaller contents. This
advantage makes it possible to avoid the preparation and the
isolation of the oxalate of the compound of formula I, which
operation presents numerous problems on the industrial scale.
In addition, the use of the non-isolated compounds of
formula I in a process for the preparation of the
pharmacologically active aminoalkoxybenzoyl-benzofuran
derivatives of the patent EP 0 471 609 and in particular in a
process for the preparation of the compounds of formula III
above makes it possible to very significantly improve the yield
of this process. In the specific case of dronedarone, the
overall yield of its synthesis, starting from its corresponding
5-nitrobenzofuran derivative, rises from 60%, according to the
state of the art, to 95% by the use of the chemos elective
process of the invention. This improvement is related in
particular to the absence of isolation of the oxalate of the
compound of formula I and to the losses associated therewith.

CLAIMS
1. A process for the preparation of 5-amino-benzoyl-benzofuran
derivatives of general formula:

in which R1 represents hydrogen or an alkyl group and R2
represents hydrogen or an alkyl, alkoxy or dialkylaminoalkoxy
group, characterized in that a 5-nitrobenzofuran derivative of
general formula:

in which R1 and R2 have the same meanings as above, is reduced
by means of a hydrogen-transfer agent, in the presence of
palladium-on-charcoal as catalyst and in an ether or a mixture
of ethers as solvent, which forms the desired compounds.
2. A process for the preparation of sulfonamidobenzofuran
derivatives of general formula:


and of their pharmaceutically acceptable salts, in which R1
represents hydrogen or an alkyl group, R2 represents hydrogen or
an alkyl, alkoxy or dialkylaminoalkoxy group and R3 represents
an alkyl group, characterized in that:
a) a 5-nitrobenzofuran derivative of general formula:

in which R1 and R2 have the same meanings as above, is reduced
by means of a hydrogen-transf er agent, in the presence of
palladium-on-charcoal as catalyst and in an ether or a mixture
of ethers as solvent, in order to form a reaction medium
comprising a 5-amino-benzoyl-benzofuran derivative, in the free
base form, of general formula:

in which R1 and R2 have the same meanings as above,
b) the reaction medium comprising the 5-amino-benzoyl-
benzofuran derivative of formula I in the free base form
obtained above is treated with a halide of general formula:

in which Hal represents a halogen and R3 has the same meaning as
above, in the presence of a basic agent, in order to obtain the
desired compounds in the free base form, which are reacted, if
necessary, with an organic or inorganic acid in order to form a
pharmaceutically acceptable salt of this desired compound.

3. The process as claimed in claim 1 or 2, characterized in
that:
• R1 represents a linear or branched C1-C8 alkyl group,
• R2 represents a linear or branched C1-C9 alkyl group, a
linear or branched C1-C8 alkoxy group or a dialkylaminoalkoxy
group in which each linear or branched alkyl group is a C1-C8
alkyl group and the linear or branched alkoxy group is a C1-C8
alkoxy group,
• R3 represents a linear or branched C1-C8 alkyl group.
4. The process as claimed in claim 1 or 2, characterized in
that:
• R1 represents a linear or branched C1-C4 alkyl group,
• R2 represents a linear or branched C1-C4 alkyl group, a
linear or branched C1-C4 alkoxy group or a dialkylaminoalkoxy
group in which each linear or branched alkyl group is a C1-C4
group and the linear or branched alkoxy group is a C1-C4 group,
• R3 represents a linear or branched C1-C4 alkyl group.
5. The process as claimed in one of claims 1 to 4, characterized
in that R1 represents n-butyl, R2 represents 3-[di(n-
butyl)amino]propoxy and R3 represents methyl.
6. The process as claimed in one of claims 1 to 5,
characterized in that the hydrogen-transfer agent is a formate
or a phosphinate.
7. The process as claimed in claim 6, characterized in that the
formate is ammonium formate and the phosphinate is sodium
phosphinate.
8. The process as claimed in one of claims 1 to 7,
characterized in that the hydrogen-transfer agent is used in
excess with respect to the compound of formula II.
9. The process as claimed in claim 8, characterized in that the
hydrogen-transfer agent is used in a proportion of 5
equivalents per equivalent of compound of formula II.
10. The process as claimed in one of claims 1 to 9,
characterized in that the ether is a dialkyl ether, a cyclic
ether or a mixture of these.

11. The process as claimed in claim 10, characterized in that
the dialkyl ether is methyl tert-butyl ether and the cyclic
ether is tetrahydrofuran.
12. The process as claimed in one of claims 1 to 11,
characterized in that the reduction takes place at a
temperature ranging from ambient temperature to 50°C to 60°C.
13. The process as claimed in one of claims 1 and 3 to 12 for
the preparation of 2-(n-butyl)-3-(4-{3-[di(n-
butyl)amino]propoxy}benzoyl)-5-aminobenzofuran, characterized
in that 2-(n-butyl)-3-(4-{3-[di(n-butyl)amino]propoxy}benzoyl)-
5-nitrobenzofuran is reduced by means of ammonium formate or
sodium phosphinate as hydrogen-transfer agent, in the presence
of palladium-on-charcoal as catalyst and in methyl tert-butyl
ether or a mixture of methyl tert-butyl ether and of
tetrahydrofuran as solvent, to form 2-(n-butyl)-3-(4-{3-[di(n-
butyl}amino]propoxy}benzoyl)-5-aminobenzofuran in the free base
form.
14. The process as claimed in one of claims 2 and 3 to 12 for
the preparation of 2-(n-butyl)-3-(4-{3-[di(n-
butyl)amino]propoxy}benzoyl)-5-(methanesulfonamido)benzofuran
or dronedarone and of its pharmaceutically acceptable salts,
characterized in that:
a) 2-(n-butyl)-3-(4-{3-[di(n-butyl)amino]propoxy}benzoyl)-5-
nitrobenzofuran is reduced by means of ammonium formate or
sodium phosphinate as hydrogen-transfer agent, in the presence
of palladium-on-charcoal as catalyst and in methyl tert-butyl
ether or a mixture of methyl tert-butyl ether and of
tetrahydrofuran as solvent, in order to form 2-(n-butyl)-3-(4-
{3-[di(n-butyl)amino]propoxy}benzoyl)-5-aminobenzofuran in the
free base form,
b) the reaction medium comprising the 2-(n-butyl)-3-(4-{3-
[di(n-butyl)amino]propoxy}benzoyl)-5-aminobenzofuran in the
free base form obtained above is treated with a methanesulfonyl
halide in the presence of a basic agent, in order to obtain the
dronedarone in the basic form, which is reacted, if necessary,

with an organic or inorganic acid in order to form a
pharmaceutically acceptable salt of dronedarone.
15. A reaction medium, characterized in that it is formed:
a) of a 5-nitrobenzofuran derivative of general
formula:

in which R1 represents hydrogen or an alkyl group and R2
represents hydrogen or an alkyl, alkoxy or dialkylaminoalkoxy
group,
c) of a hydrogen-transfer agent,
d) of palladium-on-charcoal,
e) of an ether or of a mixture of ethers, as solvent.
16. The reaction medium as claimed in claim 15, characterized
in that R1 represents n-butyl and R2 represents 3-[di(n-
butyl)amino]propoxy.